Current literature supports the concept that mast cells (MCs) play a relevant role in fighting infections in general, and our recently published data confirms that MCs play an important role in fighting viral pathogens. Despite their importance in innate and acquired immunity, mast cell development and migration into the skin is not well understood. Our findings suggest that the skin microbiome has a strong influence on migrating MCs into the skin. Our preliminary data provide evidence that the presence of bacterial products at the skin surface participates in the regulation of MC antimicrobial functions, driving them to the skin, and synergistically helping them respond to their survival growth factor, SCF. We hypothesize that TLR2 microbiome products have a unique role in MC recruitment at the outside skin interface and define the environment that directs mast cell trafficking and antimicrobial maturation. In Aim 1 we will define the interactions between the skin microbiome and MC innate immune responses in-vivo, with relevance for human pharmacology. In Aim 2 we will analyze molecular mechanisms governing the crosstalk between TLR2 signals released by the skin microbiome and MC innate immune responses, with direct application to human MCs. In Aim 3 we will determine the impact of TLR2 activation on the SCF response and MC maturation with direct correlation of MC antimicrobial functions. At the conclusion of these studies, we will have expanded our knowledge of important new aspects of MC functions and recruitment, evaluated new in-vivo models of interaction between Mast Cells and Commensal bacteria, identified candidate strategies to improve these interactions, and developed new tools for continued investigation into the pathogenesis of MC disorders. More specifically, this work has implications for fighting infections, psoriasis, and atopic dermatitis (eczema), with longer term significance fr asthma and hay fever.